The body is composed of various tissue microenvironments many of which are in close apposition with distinct commensal niches. We and others demonstrated that, in the gut, the microbiota was required for the induction of protective responses to pathogens. Outside of the gastrointestinal (GI) tract, the role of resident commensals had not been explored. Our work reveal that immunity of each barrier site is controlled in a unique manner by its resident commensals. Sites colonized by commensals are also primary targets of infections. It is estimated that in the US, a child will suffer 10 to 15 diarrheal episodes on average before the age of 5. Under steady state conditions, various layers of structural and immunological mechanisms are in place to limit host contact with the microbiota and to maintain tolerogenic responses to commensals. We found that during acute mucosal infection, commensals can be found in tight contact with the gut epithelium and translocate to peripheral tissues. We identified a novel mechanism by which the host eliminate the outgrowth of commensals during infection.